Spontaneous preterm birth (PTB; delivery before 37 weeks gestation) is a primary risk factor for infant morbidity and mortality. The etiology is unclear, but there is evidence that there is a genetic predisposition to PTB. Armed with the suggestion of genetic risk factors and the failure to identify useful biomarkers, investigators are starting to actively pursue the role of genetic predisposition in PTB. Several studies have been done to date assessing the role of single gene variants. However, positive findings have failed to replicate. We argue that heterogeneity in study designs, definition of phenotype, single-nucleotide polymorphism (SNP) selection, population selection, and sample size makes data interpretation difficult in complex phenotypes such as PTB. In this review, we introduce general concepts of study designs in genetic epidemiology, selection of candidate genes and markers for analysis, and analytical methodologies. We also introduce how the concept of gene-gene interactions (biologic epistatis) and gene-environment interactions may affect the predisposition to PTB.
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